Improved Muscle Metabolism by Combination of Muscle Activation and Protein Substitution ( IMEMPRO )

Improved Muscle Metabolism by Combination of Muscle Activation and Protein Substitution: a Randomized, Outcome-assessor Blinded, Proof-of-concept Study (IMEMPRO)

Intensive Care Unit Acquired Weakness (ICUAW) describes muscle weakness that occurs in around 40% of patients during an intensive care stay. The morbidity and mortality of these patients is significantly increased over a 5-year period. The aim of this study is to investigate the combined effect of early enteral high-protein nutrition and early muscle activation on muscle atrophy in critically ill patients.

The study will include 40 patients (20 intervention, 20 observation) with requirement for enteral nutrition at time of inclusion. In the intervention group the maximum possible level of mobilization is carried out and muscles are activated twice a day using neuromuscular electrical stimulation (NMES). The nutrition plan of the intervention group is based on the applicable guidelines for intensive care medicine with exception of increased protein intake. The control group receives therapy without deviating from the standard according of the DGEM guideline.

The study aims to show that the decrease in muscle mass is significantly less than in the control group (primary hypothesis) via ultrasound of the rectus femoris muscle and in case of given consent muscle biopsy. As secondary hypothesis it is examined whether the combination of early high protein intake and muscle activation improves muscle strength and endurance.

Study Overview

• Status: Recruiting
• Conditions: Quality of Life; Muscle Atrophy; Metabolic Disturbance; ICU Acquired Weakness; Energy Malnutrition Protein; Morphological and Microscopic Findings
• Intervention / Treatment: Dietary supplement: Dietary Supplement: additional substitution of protein; Device: Neuromuscular electrical stimulation; Other: Early Mobilization

Detailed Description

Intensive Care Unit Acquired Weakness (ICUAW) describes the clinically diagnosed manifestation of a neuromuscular organ dysfunction. It develops in approximately 40% of all intensive care unit patients amounting to at least 1.2 million patients annually in Germany. All these patients face a broad range of sequeleae and an increased mortality up to 5 years after ICU discharge. A characteristic pathophysiological phenomenon is an early severe muscle atrophy reaching 10% during the first days after ICU admission.

The current preventative and therapeutic approach for ICUAW is a combination of targeted risk factor management as well as early activation of muscles, i.e. neuromuscular electrical stimulation (NMES) and early mobilization as they have been shown to counteract the muscle atrophy and mediate different outcome benefits such as shorter ICU stay.

Nutrition is a key element of our daily life. Protein intake has been shown to affect lean mass and muscle mass. Research into specific nutritional strategies to treat or prevent ICUAW are scarce and the combination with early muscle activation has not been adequately explored.

The study will include 40 patients (20 intervention, 20 observation) who were admitted to an intensive care unit within the last 48 hours. A basic requirement for inclusion is an indication for enteral (via the gastrointestinal tract) nutrition at time of inclusion. In the intervention group, the ability to mobilize is assessed daily and the maximum possible level of mobilization is carried out and additional muscles are activated twice a day using neuromuscular electrical stimulation (NMES). The nutrition plan of the intervention group is based on the applicable guidelines for intensive care medicine. In this study, protein intake is increased in the interventional group. The control group receives therapy without deviating from the standard according to the SOP and DGEM guideline: "Clinical nutrition in intensive care medicine" 2018.

The study aims to show that the decrease in muscle mass is significantly less than in the control group (primary hypothesis) via ultrasound of the rectus femoris muscle and muscle biopsy. As a second hypothesis it is examined whether the combination of early high protein intake and muscle activation improves muscle strength and endurance compared to the control group.

Further exploratory analyses will investigate changes in the skeletal muscle glycogen content, skeletal muscle histology, skeletal muscle gene expression, skeletal muscle protein level, as well as metabolomic changes in blood and urine.

An additional blood sample will be taken after 90 days as part of a follow-up.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Stefan J Schaller, MD; Phone Number: +498941409635; Email: s.schaller@tum.de
• Study Contact Backup: Name: Kristina Fuest, MD; Email: kristina.fuest@tum.de

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Recruiting
    • Charité - Universitätsmedizin Berlin
    • Contact: Stefan J Schaller, MD; Phone Number: +49-30-450-531052; Email: stefan.schaller@charite.de
  • Bavaria
    • Munich, Bavaria, Germany, 81675
      • Recruiting
      • Klinikum rechts der Isar, School of Medicine, Technical Universtity of Munich
      • Contact: Kristina Fuest, MD; Email: kristina.fuest@tum.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• critically ill adults (≥ 18 years of age)
• newly admitted to the ICU (<48h)
• mechanically ventilated, expected to remain for at least 72h
• enteral nutrition is feasible

Exclusion Criteria:

• a BMI > 30
• expected death or withdrawal of life-sustaining treatments
• prior neuromuscular disease (e.g. paresis, myopathies, neuropathies)
• injury or disease preventing neuromuscular electrical stimulation or early mobilization (e.g., elevated intracranial pressure, unstable spine)
• a pacemaker or other electronic implant
• allergy to components of NMES adhesive
• have been dependent during activities of daily living prior to the hospital admission
• a language barrier

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention; High protein substitution plus NMES and EM	Dietary supplement: Dietary Supplement: additional substitution of protein; Day one (admission) no nutrition is applied. Protein target is increased as follows: to a level of 1,2g/kg/d on day 1 after ICU admission; to a level of 1,4g/kg/d on day 2 after ICU admission; to a level of 1,6g/kg/d on day 3 after ICU admission; to a level of 1,8g/kg/d on day 4 after ICU admission; to a level of 2,0g/kg/d from day 5 onwoards Additional protein is given within 2 hours after mobilization respectively: to 0,125g/kg/d on day 1 after ICU admission; to 0,2g/kg/d on day 2 after ICU admission; to 0,25g/kg/d on day 3 after ICU admission; to 0,3g/kg/d from day 4 after ICU admission onwoards; Device: Neuromuscular electrical stimulation; twice daily 60 minutes till day 28 or ICU discharge; Other: Early Mobilization; at least 20 minutes a day following the SOMS concept. Duration: till 28 day or ICU discharge
No Intervention: Control Group; Nutrition and mobilization are carried out according to standard of care.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in cross sectional area (ΔCSA) of the rectus femoris	Change in muscle mass between study inclusion and study day 14; measured as change of the cross sectional area (ΔCSA) of the rectus femoris muscle via ultrasound.	day 1 (study inclusion) and 14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in muscle thickness of the rectus femoris	change in muscle thickness from study inclusion until 90-day follow-up, measured via ultrasound.	day 1 (study inclusion) until 90-day Follow-up
change in echogenicity of the rectus femoris	change in echogenicity from study inclusion until 90-day follow-up, measured via ultrasound.	day 1 (study inclusion) until 90-day Follow-up
change of the pennation angle of the rectus femoris	change of the pennation angle from study inclusion until 90-day follow-up, measured via ultrasound.	day 1 (study inclusion) until 90-day Follow-up
change of the muscle strength, measured by the Medical Research Council score (MRC-score)	change of the muscle strength, measured by the Medical Research Council score (MRC-score) from study inclusion until 90-day follow-up	day 1 (study inclusion) until 90-day Follow-up
change of the muscle strength, measured by handgrip dynamometry	change of the muscle strength, measured by handgrip dynamometry from study inclusion until 90-day follow-up	day 1 (study inclusion) until 90-day Follow-up
change in muscle endurance	change in muscle endurance, measured by the 6-minute walking test up to 90-day follow-up	up to 90 day follow up
change in physical physical function	change in physical physical function, measured by the Short Physical Performance Battery up to 90-day follow-up	up to 90-day follow-up
development of quality of life	development of quality of life, measured by the Short Form-36 up to 90-day follow-up	up to 90-day follow-up
change in Skeletal muscle mass	change in Skeletal muscle mass, measured with bioelectrical impedance analysis up to 90-day follow-up.	day 1 (study inclusion) until 90-day Follow-up
change in extracellular volume	change in extracellular volume, measured by the Body impedance analysis	day 1 (study inclusion) until 90-day Follow-up
change in the REE (Resting Energy Expenditure)	change in the REE (Resting Energy Expenditure), measured by indirect calorimetry	day 1 (study inclusion) until 90-day Follow-up
urea-to-creatinine ratio	urea-to-creatinine ratio from blood sample	day 1 (study inclusion) until 90-day Follow-up
Identify possible predictors of muscle wasting in urine metabolomics at ICU admission	Among the urine metabolomics that will be measured, identify metabolites or combinations of metabolites whose high or low concentration(s) at ICU admission associate(s) with the amount of muscle loss. These metabolites are candidate biomarkers that could be used to identify individuals at risk of large muscle wasting and may give further insights into the mechanisms of muscle wasting.	day 1 (study inclusion) until 90-day Follow-up
Identify possible predictors of muscle wasting in the blood metabolome at ICU admission	Among the blood metabolome that will be measured, identify metabolites or combinations of metabolites whose high or low concentration(s) at ICU admission associate(s) with the amount of muscle loss. These metabolites are candidate biomarkers that could be used to identify individuals at risk of large muscle wasting and may give further insights into the mechanisms of muscle wasting.	day 1 (study inclusion) until 90-day Follow-up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
in-hospital mortality	Mortality during the Hospital stay	until 90-day Follow-up
Hospital LOS	Length of stay in the hospital	until 90-day Follow-up
ICU-LOS	Length of stay in the ICU	until 90-day Follow-up
Hospital mortality	Mortality during Hospital stay	until 90-day Follow-up
Duration of Mechanical ventilation	Duration of invasive mechanical ventilator dependency	until 90-day Follow-up
ICU mortality	Mortality during ICU stay	until 90-day Follow-up
enzyme function in the rectus femoris	Spectrophotometry will be done in muscle samples. All samples will be screened for influence of Intensive Care Unit Acquired Weakness (ICUAW) and correlation with blood metabolome changes.	according to biopsy inbetween day 1-7
protein content in the rectus femoris	Western Blot will be done in muscle samples. All samples will be screened for influence of Intensive Care Unit Acquired Weakness (ICUAW) and correlation with blood metabolome changes.	according to biopsy inbetween day 1-7
geneexpression in the rectus femoris	qPCR (quantitive polymerase chain reaction) will be done in muscle samples. All samples will be screened for influence of Intensive Care Unit Acquired Weakness (ICUAW) and correlation with blood metabolome changes.	according to biopsy inbetween day 1-7
Muscle morphology of the rectus femoris	Light-and Electron-Microscopy will be done in muscle samples. All samples will be screened for influence of Intensive Care Unit Acquired Weakness (ICUAW) and correlation with blood metabolome changes.	according to biopsy inbetween day 1-7

Collaborators and Investigators

• Sponsor: Technical University of Munich
• Collaborators: University Medicine Greifswald; Fresenius Kabi; Berlin Institute of Health
• Investigators: Principal Investigator: Stefan J Schaller, MD, TUM, Germany & Charité - Universitätsmedizin Berlin

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2023
• Primary Completion (Estimated): October 31, 2024
• Study Completion (Estimated): January 15, 2025

Study Registration Dates

• First Submitted: June 6, 2023
• First Submitted That Met QC Criteria: June 15, 2023
• First Posted (Actual): June 27, 2023

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 3, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Early Mobilization and high-protein nutrition
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Nutrition Disorders; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Deficiency Diseases; Atrophy; Protein Deficiency; Muscular Atrophy; Malnutrition; Protein-Energy Malnutrition
• Other Study ID Numbers: IMEMPRO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified data can be requested on reasonable scientific request and data sharing contract, if necessary.
• IPD Sharing Time Frame: After publication of scientific manuscript.
• IPD Sharing Access Criteria: Deidentified data can be requested on reasonable scientific request and data sharing contract, if necessary.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No